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Research
C
lostridium difficile
–associated disease (CDAD) is
endemic in Canadian hospitals. In 1995 its nation-
wide incidence was estimated at 3.6 per 10 000 pa-
tient-days.
1
Since the end of 2002, an epidemic of CDAD
caused by a hypervirulent strain of
C. difficile
has spread into
many hospitals in the province of Quebec, especially in the
Montréal area.
2–8
In January 2005, 30 hospitals in Quebec had
a rate of nosocomial CDAD higher than 15 per 10 000 patient-
days.
6
In Sherbrooke, a city 140 km southeast of Montréal, the
incidence among people aged 65 years or more increased 10-
fold between 1991 and 2003, reaching a rate of 866.5 per
100 000 inhabitants, mostly through nosocomial transmis-
sion.
4
The predominant strain in Quebec is a hyperproducer
of toxins A and B,
9
inducing severe diarrhea that may facili-
tate its transmission by incontinent patients. Other factors
that have potentially contributed to the emergence of this
strain are the increasing size of the population of elderly in-
patients with numerous comorbidities, chronic underinvest-
ment in hospital infrastructures, suboptimal response to
metronidazole therapy, with frequent recurrences, and resist-
ance to fluoroquinolones, which became potent inducers of
CDAD.
4,10–12
The same toxinotype III ribotype 027 hyperviru-
lent strain has now been found in the United States, the
United Kingdom and the Netherlands.
13–16
A high short-term mortality was noted among CDAD pa-
tients in Sherbrooke, where 13.8% died within 30 days after
diagnosis in 2003, compared with 4.7% in 1991/92 (these fig-
ures included both community-acquired and nosocomial
cases).
4
The proportion of deaths attributable to CDAD re-
mains unknown, as does the excess mortality that might
occur beyond the initial month after diagnosis. We thus con-
ducted this study to measure mortality attributable to no-
socomial CDAD, as well as the impact of CDAD on length of
hospital stay, during 2003 and 2004 at the Centre hospitalier
universitaire de Sherbrooke (CHUS), a 683-bed tertiary care
hospital.
Methods
A database comprising all cases of CDAD diagnosed at CHUS
since 1991 is regularly updated by review of laboratory reports
and discharge diagnoses and by periodic searches of the hospi-
tal’s computerized medical records.
4,11
The CHUS laboratory is
the only one in the region performing the
C. difficile
cytotoxin
assay. We considered a patient to have CDAD if he or she had
diarrhea and met at least one of the following criteria: a stool
specimen positive for
C. difficile
toxin by means of cytotoxin
assay; changes on colonoscopy typical of pseudomembranous
colitis; and histopathologic evidence of pseudomembranous
CMAJ • October 25, 2005 • 173(9) | Online-1
© 2005 CMA Media Inc. or its licensors
DOI:10.1503/cmaj.050978
Jacques Pépin, Louis Valiquette, Benoit Cossette
Fast-tracked article. Early release, published at www.cmaj.ca on Sept. 22, 2005. Revised Sept. 29, 2005
Mortality attributable to nosocomial
Clostridium
difficile
–associated disease during an epidemic caused
by a hypervirulent strain in Quebec
Background: Since 2002 an epidemic of
Clostridium
difficile
–associated disease (CDAD) caused by a hyperviru-
lent toxinotype III ribotype 027 strain has spread to many
hospitals in Quebec. The strain has also been found in the
United States, the United Kingdom and the Netherlands.
The effects of this epidemic on mortality and duration of
hospital stay remain unknown. We measured these effects
among patients admitted to a hospital in Quebec during
2003 and 2004.
Methods: We compared mortality and total length of hospital
stay among inpatients in whom nosocomial CDAD developed
and among control subjects without CDAD matched for sex,
age, Charlson Comorbidity Index score and length of hospital
stay up to the diagnosis of CDAD in the corresponding case.
Results: Thirty days after diagnosis 23.0% (37/161) of the pa-
tients with CDAD had died, compared with 7.0% (46/656) of
the matched control subjects (
p
< 0.001). Twelve months after
diagnosis, mortality was 37.3% (60/161) among patients with
CDAD and 20.6% (135/656) among the control subjects (
p
<
0.001), for a cumulative attributable mortality of 16.7% (95%
confidence interval 8.6%–25.2%). Each case of nosocomial
CDAD led, on average, to 10.7 additional days in hospital.
Interpretation: This study documented a high attributable
mortality among elderly patients with CDAD mostly caused
by a hypervirulent strain, which represents a dramatic change
in the severity of this infection.
ABSTRACT:
Cite this article as
CMAJ
2005;173(9). DOI:10.1503/cmaj.050978
colitis. We considered a case of CDAD to be nosocomial if it
developed more than 72 hours after hospital admission and up
to 2 months after hospital discharge; all others were consid-
ered community-acquired cases.
We nested the current analysis within a cohort study of
CHUS inpatients (aiming to identify risk factors for nosoco-
mial CDAD), in which we reviewed the medical records of all
adult patients admitted to hospital at least once in internal
medicine, family medicine or gastroenterology wards be-
tween January 2003 and June 2004 and a random sample of
50% of patients admitted to hospital in the general surgery
ward, as described in detail elsewhere.
12
For each patient, we
reviewed all hospital admissions during that period, regard-
less of the admitting service. Multiple hospital admissions for
the same patient were considered to be a single “episode of
care” if the interval between dates of discharge and subse-
quent readmissions was 60 days or less.
12
Hospital admis-
sions separated by more than 60 days were considered to be
distinct episodes of care. To quantify the overall burden of co-
morbidities, we used the Charlson Comorbidity Index score,
validated in numerous studies as a predictor of health care
costs and mortality.
17–20
The whole cohort comprised 5619
patients with 7421 episodes of care; for 5091 of the episodes
of care, the patient was admitted only once, and for 2330 the
patient was admitted 2 or more times.
12
As shown in Table 1,
the duration of hospital stay, per episode of care, and mortal-
ity were strongly influenced by age and Charlson Comorbidity
Index score, as expected, which justified their subsequent use
as matching criteria. Furthermore, within each age group or
comorbidity index stratum, mortality was higher among pa-
tients who stayed longer in hospital (data not shown).
We included as case subjects only patients whose CDAD was
diagnosed within an episode of care (a) during the first hospital
admission, if the diagnosis was made more than 72 hours after
admission, or (b) in the interval between the first
and second hospital admissions or (c) during the
first 3 days after the second hospital admission.
We excluded patients whose CDAD was diag-
nosed less than 72 hours after their first hospital
admission. In other words, we included only pa-
tients presumably exposed to
C. difficile
during
their first hospital admission within an episode of
care. Of 293 incident cases of CDAD in the whole
cohort, 185 fulfilled this definition.
We wanted the control subjects to be as simi-
lar as possible to the case subjects for the pres-
ence of factors predictive of death and duration
of hospital stay. For each case subject, we ran-
domly selected up to 5 matched control subjects
among all patients who did not acquire CDAD,
were of the same sex and the same age (± 2
years), had an identical Charlson Comorbidity
Index score and had remained in hospital at
least as long as the corresponding case subject
did until his or her CDAD was diagnosed (if the
CDAD developed during the first hospital ad-
mission). For cases of CDAD that developed af-
ter the first admission, we selected similarly
matched control subjects among patients
whose duration of first hospital admission had
been similar (± 3 days) to that of the case sub-
ject. A patient could not be used as a control
subject more than once. We excluded 24 case
subjects because they had no suitable control
subjects (e.g., 12 were 85 years or older, and 11
CMAJ • October 25, 2005 • 173(9) | Online-2
Research
Editor's note
A new strain of
Clostridium difficile
has been character-
ized as a hypervirulent toxinotype III ribotype 027 strain
that produces levels of toxins A and B that are 16 to 23
times higher than those of previous toxinotype 0 strains.
Does this strain cause more serious illness?
One year after diagnosis, 37% of 161 patients with
CDAD had died, compared with 21% of 656 control sub-
jects matched for age and disease severity, for a difference
of 16.7% (95% confidence interval 8.6%–25.2%). Patients
with CDAD also had longer lengths of stay in hospital and
were more likely to undergo emergency colectomy.
Implications for practice: Although this study could not
compare the morbidity and mortality of patients with dif-
ferent strains of CDAD, it seems likely that the new strain
is substantially more lethal than previous ones.
Table 1: Duration of hospital stay, per episode of care, and mortality in a
cohort of patients admitted to the CHUS in 2003 and 2004,
11
by age and
Charlson Comorbidity Index score
No. (%) of patients who died
Charlson score;
age group
No. of
patients*
Mean
hospital
stay, d
Within
30 d after
admission
Within
1 yr after
admission
Charlson score 0
18–64 yr 1125 7.0 4 (0.4) 10 (0.9)
65–74 yr 286 8.1 5 (1.7) 12 (4.2)
≥ 75 yr
162 10.3 4 (2.5) 10 (6.2)
Charlson score 1–3
18–64 yr 1107 10.8 16 (1.4) 47 (4.2)
65–74 yr 1220 13.6 42 (3.4) 131 (10.7)
≥ 75 yr
1099 14.9 92 (8.4) 216 (19.7)
Charlson score 4–6
18–64 yr 299 15.7 14 (4.7) 39 (13.0)
65–74 yr 659 17.4 47 (7.1) 156 (23.7)
≥ 75 yr
803 19.2 82 (10.2) 214 (26.7)
Charlson score ≥ 7
18–64 yr 136 19.5 11 (8.1) 42 (30.9)
65–74 yr 292 23.0 32 (11.0) 108 (37.0)
≥ 75 yr
233 21.7 38 (16.3) 86 (36.9)
Note: CHUS = Centre hospitalier universitaire de Sherbrooke.
*The sum is greater than the total number of patients because some patients had more than one
episode of care.
had a comorbidity score of 5 or more), which left 161 cases.
We were able to find 656 control subjects.
Proportions were compared with the use of the χ
2
test or,
when numbers were small, the Fisher’s exact test. Continu-
ous data were compared with the use of Student’s
t
test or, if
not normally distributed, the Kruskal–Wallis test. The proba-
bility of death over time was compared using the Kaplan–
Meier method. For case subjects, day zero corresponded to
the date of diagnosis of CDAD, whereas for their matched
control subjects it was the day that they reached the same in-
terval since admission as their case subject. The CHUS com-
puterized medical records include the date of death even for
events that occurred outside the hospital, from data provided
by the Quebec Direction de l’État-Civil.
Results
As shown in Table 2, there were trivial differences in the sex
distribution and the Charlson Comorbidity Index scores be-
tween the case and control subjects, owing to the fact that it
was easier to find the maximal number of control subjects
among women and among patients with a low comorbidity
score. The mean age of the case and control subjects was 77.5
and 77.4 years respectively and the mean comorbidity score
3.8 and 3.5. The distribution of specific medical conditions
did not differ statistically significantly between the case and
control subjects.
Mortality among patients with CDAD and their matched
control subjects differed considerably. At 30 days, 23.0% of
the case subjects had died, compared with 7.0% of the con-
trol subjects (
p
< 0.001, χ
2
test) (Table 3). The differential
mortality increased thereafter, with 36.0% of the case sub-
jects and 14.6% of the control subjects having died at 6
months (
p
< 0.001, χ
2
test) (Fig. 1). The survival curves then
converged to some extent, and at 12 months 37.3% of the
case subjects and 20.6% of the control subjects had died, for a
cumulative 1-year attributable mortality of 16.7% (95% confi-
CMAJ • October 25, 2005 • 173(9) | Online-3
Research
Table 2: Characteristics of inpatients in whom nosocomial
Clostridium difficile-associated disease (CDAD) developed and
of matched control subjects without CDAD
Group; no. (%)
of patients
Characteristic
Case
subjects
n = 161
Control
subjects
n = 656 p value
Sex
Female 92 (57.1) 398 (60.7)
Male 69 (42.9) 258 (39.3)
0.47
Age, yr
18–64 16 (9.9) 64 (9.8)
65–74 62 (38.5) 257 (39.2)
≥ 75
83 (51.6) 335 (51.1)
0.99
Charlson score
0 11 (6.8) 55 (8.4)
1–3 69 (42.9) 305 (46.5)
4–6 59 (36.6) 225 (34.3)
≥ 7
22 (13.7) 71 (10.8)
0.60
Had surgery during episode
of care 34 (21.1) 130 (19.8) 0.80
Comorbidity
Ischemic heart disease 73 (45.3) 338 (51.5) 0.19
Congestive heart failure 23 (14.3) 134 (20.4) 0.10
Chronic renal failure 35 (21.7) 131 (20.0) 0.70
Chronic lung disease 60 (37.3) 209 (31.9) 0.22
Diabetes mellitus 40 (24.8) 186 (28.4) 0.43
Peripheral vascular
disease 66 (41.0) 221 (33.7) 0.10
Cerebrovascular disease 46 (28.6) 155 (23.6) 0.23
Dementia 28 (17.4) 85 (13.0) 0.29
Nonmetastatic solid
tumour 27 (16.8) 113 (17.2) 0.18
Metastatic solid tumour 7 (4.3) 21 (3.2) 0.63
Leukemia or lymphoma 4 (2.5) 16 (2.4) 1.00
Connective tissue disease 7 (4.3) 46 (7.0) 0.98
Severe hepatic disease 3 (1.9) 15 (2.3) 1.00
Table 3: Outcomes of inpatients in whom nosocomial
Clostridium difficile-associated disease (CDAD) developed and
of matched control subjects without CDAD
Group; no. (%)
of patients
Outcome
Case
subjects
n = 161
Control
subjects
n = 656 p value
Death
Within 30 d 37 (23.0) 46 (7.0) < 0.001
Within 90 d 48 (29.8) 75 (11.4) < 0.001
Within 6 mo 58 (36.0) 96 (14.6) < 0.001
Within 1 yr 60 (37.3) 135 (20.6) < 0.001
Duration of first hospital
admission, mean, d 25.5 18.8 < 0.001
Second admission
Did occur 60 (37.3) 151 (23.0) < 0.001
Duration, mean, d 16.8 14.4 0.59
Third admission
Did occur 17 (10.6) 39 (5.9) 0.06
Duration, mean, d 14.1 11.4 0.22
Fourth admission
Did occur 7 (4.3) 12 (1.8) 0.08
Duration, mean, d 11.1 12.7 0.42
Total duration in
hospital, mean, d 33.7 23.1 < 0.001
Admission to ICU
All causes 51 (31.7) 158 (24.1) 0.06
CDAD-related 16 (9.9) NA
CDAD-related colectomy 4 (2.5) NA
Note: NA = not applicable.
dence interval 8.6%–25.2%). Table 3 also shows the duration
of hospital stays for the case and control subjects during an
episode of care. The occurrence of CDAD increased the dura-
tion of the first admission by 6.7 days on average; it also had
an impact on the need for a second, third and fourth hospital
admission. Overall, patients with CDAD spent 10.7 days
longer in hospital than the control subjects; 9.9% needed ad-
mission to an intensive care unit for CDAD-related care
(where they spent 6.9 days on average), and 2.5% needed an
emergency colectomy (Table 3).
A total of 630 cases of nosocomial CDAD occurred among
all CHUS patients during 2003 and 2004. Extrapolating to
this group the mean excess duration of hospital stay, we cal-
culated that the epidemic generated 6716 days of hospital care
and that, on average, 9 hospital beds were used each day to
provide care to CDAD patients.
We calculated the mortality at 30 days and at 12 months
among the case and control subjects after stratifying for age
and Charlson Comorbidity Index score (Table 4). There was no
excess mortality attributable to nosocomial CDAD among pa-
tients aged less than 65 years or among those without comor-
bidities (Charlson score = 0). The attributable mortality was
substantial both among patients aged 65–74 years and among
those aged 75 years or more as well as in all 3 categories of co-
morbidity scores for patients with at least one comorbidity.
Interpretation
The most important finding of our study was the high excess
mortality among hospital patients with CDAD compared with
matched control subjects, who should otherwise have experi-
enced approximately the same mortality. This attributable
mortality appeared in the first month following diagnosis. For
many elderly patients, CDAD and its common relapses
11
lead
to a cascade of interrelated complications that are ultimately
fatal. Some outcomes occur because of a direct complication
of CDAD (septic shock, perforation), whereas for others the
pathway to death is more complex: for example, a myocardial
infarction triggered by hypovolemia, a pulmonary embolism
following prolonged immobilization, or a second nosocomial
infection. Our approach provided an estimate of the overall ex-
cess mortality attributable to CDAD among elderly patients
with several comorbidities, avoiding the biases inherent in re-
lying on a reviewer’s judgment to determine whether a given
death was caused directly or indirectly by CDAD.
7
The survival
curves in Fig. 1 suggest that, for deaths that occurred more
than 30 days after diagnosis, CDAD merely precipitated an
event that would have occurred in any case a few months later
owing to the patient’s comorbidities. However, about one-
sixth of the inpatients with CDAD died when they would have
CMAJ • October 25, 2005 • 173(9) | Online-4
Research
Fig. 1:
Kaplan–Meier plot showing probability of death since di-
agnosis among inpatients in whom nosocomial
Clostridium diffi-
cile
–associated disease (CDAD) developed and among matched
control subjects without CDAD. No. of days = time since diagno-
sis of CDAD (cases) or time since reaching the same interval after
admission (controls).
Proportion surviving
No. of days
0
0.50
0.75
1.00
100 200 400
Cases
Controls
300
Table 4: Mortality at 30 days and 1 year among inpatients in whom nosocomial Clostridium difficile-associated disease (CDAD)
developed and in matched control subjects without CDAD, by age and Charlson Comorbidity Index score
Mortality at 30 d Mortality at 1 yr
Variable
No. (%) of
case subjects
No. (%) of
control subjects
Attributable
mortality (95% CI), %
No. (%) of
case subjects
No. (%) of
control subjects
Attributable
mortality (95% CI), %
Age, yr
18–64 1/16 (6.3) 2/64 (3.1) 3.2 (–7.4 to 29.3) 1/16 (6.3) 7/64 (10.9) –4.7 (–22.0 to 17.1)
65–74 12/62 (19.4) 13/257 (5.1) 14.3 (5.0 to 26.9) 23/62 (37.1) 41/257 (16.0) 21.1 (8.4 to 35.0)
≥ 75
24/83 (28.9) 31/335 (9.3) 19.7 (9.8 to 31.2) 36/83 (43.4) 87/335 (26.0) 17.4 (5.6 to 29.6)
Charlson
Comorbidity
Index score
0 0/11 (0) 1/55 (1.8) –1.8 (–30.4 to 11.0) 0/11 (0) 1/55 (1.8) –1.8 (–30.4 to 11.0)
1–3 16/69 (23.2) 16/305 (5.2) 17.9 (8.4 to 30.1) 20/69 (29.0) 48/305 (15.7) 13.3 (2.2 to 26.2)
4–6 15/59 (25.4) 23/225 (10.2) 15.2 (4.0 to 28.9) 28/59 (47.5) 59/225 (26.2) 21.2 (6.8 to 35.6)
≥ 7
6/22 (27.3) 6/71 (8.5) 18.8 (0.4 to 42.5) 12/22 (54.5) 27/71 (38.0) 16.5 (–8.6 to 39.7)
Note: CI = confidence interval.
otherwise been expected to survive at least 1 year. This repre-
sents a major change in the epidemiology and pathogenicity of
C. difficile
, which until recently was considered a nuisance
pathogen with no measurable impact on mortality.
21
Our study had limitations. We were unable to find 5 con-
trol subjects for each case subject, which resulted in minor
differences between the case and control subjects in sex dis-
tribution and comorbidity scores. However, within the whole
cohort, mortality did not differ between men and women,
and differences in comorbidity scores between case and con-
trol subjects were probably too modest to bias our measure of
attributable mortality. Another limitation was that we nested
our current analysis within a larger cohort study examining
risk factors for CDAD among patients admitted to hospital at
least once in internal medicine, family medicine, gastroen-
terology or general surgery wards. In our hospital, patients
admitted to these wards are older than those admitted by
other medical or surgical subspecialty services (mean 65.8 v.
58.4 years). As a consequence, the mean age of the 161 case
subjects in the current study was 77.4 years, compared with
72.3 years for all 630 cases of nosocomial CDAD diagnosed at
the CHUS during 2003 and 2004. Many cases of nosocomial
CDAD and of CDAD-attributable deaths occurred in very old,
debilitated patients for whom the attending physician and the
family jointly decided not to provide aggressive care. We
might have calculated a somewhat lower attributable mortal-
ity had we conducted the study within a cohort of all adult,
nonpsychiatric, nonobstetric admissions, thus including pa-
tients less than 65 years of age with fewer comorbidities for
whom intensive care (or a colectomy) would be contem-
plated. However, the 30-day all-cause mortality of 23.0%
among the cases of nosocomial CDAD in the current analysis
was identical to that among all nosocomial CDAD cases re-
ported by the Quebec provincial surveillance system.
7
We measured the attributable mortality during an epi-
demic of CDAD caused by a hypervirulent toxinotype III ribo-
type 027 strain, which produced levels of toxins A and B
16–23 times higher than those of contemporary toxinotype 0
strains and represented two-thirds of our isolates of hospital-
acquired
C. difficile
.
9
Thus, our results cannot be extrapo-
lated to centres outside Quebec, where the strain might be ab-
sent or uncommon. However, the same strain has been found
in several US states and more recently in the United Kingdom
and the Netherlands.
14–16
In England, Wales and Northern
Ireland, the number of cases of CDAD reported doubled be-
tween 2001 and 2004;
13
in 2004, the nationwide incidence of
CDAD among people aged 75 years or more was 678 per
100 000,
13,14
and the rates of nosocomial CDAD were similar
to those reported in Quebec.
22
Although improved reporting
might explain some of this rising incidence, preliminary evi-
dence suggests that the ribotype 027 strain has spread to at
least 15 hospitals in the United Kingdom.
23
Because the risk of CDAD is influenced by the duration of
hospital stay (which reflects exposure),
12
a longer hospital
stay could be the cause rather than the consequence of CDAD.
To avoid such a bias, we selected as case subjects only pa-
tients who had probably been exposed to
C. difficile
during
their first hospital admission within an episode of care, and
as control subjects only patients without CDAD who had been
in hospital at least as long as their matched case subject had
been until the day CDAD was diagnosed. Previous studies of
the effect of CDAD on costs and durations of hospital stay did
not distinguish between the time that case subjects spent in
hospital before and after the diagnosis of CDAD.
21,24,25
Despite the limitations of our study, our results can be
used to estimate the approximate total excess mortality
caused by the
C. difficile
epidemic in Quebec (population
7.5 million). A review of an administrative database of the
Quebec ministry of health
5
revealed that 7731 cases of no-
socomial CDAD were documented during the fiscal year
2003/04. Data for 2004/05 are not yet known, but preliminary
results from a provincial surveillance system suggest that the
incidence was similar.
7
Based on a conservative estimate of
14 000 cases of nosocomial CDAD for these 2 years and the
95% confidence intervals around our measures of attributable
mortality, and assuming that throughout Quebec 75% of the
cases of nosocomial CDAD occur among patients aged 65
year or more, we calculated that, for the whole of Quebec, be-
tween 1000 and 3000 patients might have died so far as a re-
sult of this epidemic.
A lingering question that remains unanswered is why this
strain of
C. difficile
spread so extensively within and between
hospitals in Quebec, while dissemination of the same hyper-
virulent, and presumably highly infectious, strain seems to
have been more limited in the rest of Canada and the United
States.
15,26,27
There is no evidence that Quebec differs from
other jurisdictions in North America with regard to the size of
its population of elderly inpatients or to the use of antibiotics.
In 2003 and 2004, respectively, 686 and 663 prescriptions of
antibiotics per 1000 inhabitants were delivered in retail phar-
macies of Quebec, compared with 763 and 737 in the rest of
Canada.
28
Assuming a mean duration of 10 days per prescrip-
tion, use of antibiotics in Quebec corresponded to 18.5 de-
fined daily doses per 1000 inhabitants-days, a figure similar
to that in British Columbia
29
and to the median in 26 Euro-
pean countries.
30
The lack of investment in our hospitals in-
frastructure over several decades, with shared bathrooms be-
ing the rule rather than the exception, may have facilitated the
transmission of this spore-forming pathogen, which can sur-
vive on environmental surfaces for months. Providing mod-
ern medical care within hospitals built a century ago is no
longer acceptable.
CMAJ • October 25, 2005 • 173(9) | Online-5
Research
Competing interests: None declared.
This article has been peer reviewed.
From the Department of Microbiology and Infectious Diseases, University of
Sherbrooke (Pépin, Valiquette), and the Department of Pharmacy, Centre
hospitalier universitaire de Sherbrooke (Cossette), Sherbrooke, Que.
Contributors: Jacques Pépin was responsible for the conception of the study,
supervised data collection, conducted the analyses and wrote the first draft of
the manuscript. Louis Valiquette and Benoit Cossette contributed to data
analysis and revised subsequent versions of the manuscript. All of the au-
thors contributed to the final version of the manuscript.
Acknowledgements: We are indebted to Bruno Hubert, Philippe De Wals and
Clifford McDonald for their thoughtful comments on an earlier draft of this
manuscript.
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CMAJ • October 25, 2005 • 173(9) | Online-6
Research
Correspondence to: Dr. Jacques Pépin, Centre hospitalier
universitaire de Sherbrooke, 3001, 12
e
Avenue Nord, Sherbrooke
QC J1H 5N4; fax 819 820-6451; jacques.pepin@usherbrooke.ca
